Benzothiadiazine-1, 1-dioxides



United States Patent 3,210,347 BENZOTI-IIADIAZINE-1,1-DIOXIDES LincolnHarvey Werner, Summit, and George de Stevens, New Providence, N.J.,assignors to Ciba Corporation, a corporation of Delaware No Drawing.Filed July 12, 1961, Ser. No. 123,418 Claims. (Cl. 260-243) The presentinvention concerns S-carbocyclic aryl-loweralkyl-1,2,4-benzothiadiazine-1,1-dioxides. More particularly, it relatesto compounds having one of the formulae:

s 7 I IH Rz' g n 2n) Rl 3 and \N R: I l! n 2n) l H in which the letter11 stands for one of the whole numbers 1, 2, 3 and 4, R representsmonocyclic carbocyclic aryl, and R stands for hydrogen, halogeno, loweralkyl, trifiuoromethyl and nitro, or salts of such compounds, as well asprocess for the preparation thereof.

The letter n stands primarily for l, but may also represent one of thenumbers 2, 3 and 4. The group of the formula -(C H may, therefore,represent lower alkylene having from one to four carbon atoms, primarilymethylene, as well as 1,1-ethylene, 1;,2-ethylene, 1,1-propylene,1,2-propylene, 2,2-propylene, 2,3-propylene, 1,3- propylene,1,1-butylene, 1,4-butylene and the like.

The monocyclic carbocyclic aryl portion R represents primarily phenyl;it may also stand for substituted phenyl, such as lower alkyl-phenyl,e.g. 4-methyl-phenyl, 3,4-dimethyl-phenyl, Z-ethyl-ph'enyl,4-isopropyl-pheny1 and the like, etherified hydroXy-phenyl, particularlylower alkoXy-phenyl, e.g. 4-methoxyphenyl, 3,4,5-trimethoxyphenyl,3-ethoXy-phenyl, 4-secondary butyloxy-phenyl and the like,halogeno-phenyl, e.g. 4-fluoro-phenyl, 4- chloro-phenyl,2,5-dichloro-phenyl, 3-bromo-p'henyl and the like,trifluoromethyl-phenyl, e.g. 4-trifluoromethylphenyl and the like, orany other suitably substituted phenyl group.

The group R which is preferably attached to the 6- position or the7-position of the 1,2-4-benzothiadiazinel,l-dioxide nucleus, mayrepresent hydrogen, nitro or lower alkyl having from one to four carbonatoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondarybutyl, tertiary butyl and the like. However, R represents primarilytrifluoromethyl or halogeno, especially halogeno having an atomic weightbetween 35 and 80, i.e. chloro or bromo, as well as fluoro and the like.

Salts of the compounds of this invention are primarily alkali metal,e.g. sodium, potassium and the like, or alkaline earth metal, e.g.magnesium, calcium and the like, salts thereof.

The compounds of this invention counteract'the eifect of physiologicalpressure agents, such as epinephrine, norepinephrine or hypertensivepolypeptides, e.g. angiotensin-II-amide and the like, and thus cause alowering of the blood pressure. They can, therefore, be used asantihypertensive agents to relieve hypertensive conditions, such asrenal hypertension, essential hypertension, malignant hypertension andthe like.

3,210,347 Patented Oct. 5, 1965 Particularly useful are the compoundshaving one of the formulae:

in which one of the groups R and R represents chloro, bromo ortrifluoromethyl, and the other stands for hydrogen or methyl, or thealkali metal, e.g. sodium, potassium and the like, salts thereof.

The new compounds of this invention may be used in the form ofpharmaceutical preparations, which contain the new 3-carbocyclicaryl-lower alkyl-1,2,4-benzothiadiazine-l,l-dioxides or salts thereof inadmixture with a pharmaceutical organic or inorganic, solid or liquidcarrier suitable for enteral or parenteral administration. For making upthe preparations there can be employed substances which do not reactwith the new compounds, such as water, gelatine, lactose, starches,stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils,benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols orany other known carrier used for pharmaceutical preparations. The lattermay be in solid form, for example, as capsules, tablets, dragees and thelike or in liquid form, for example, as solutions, suspensions,emulsions and the like. If necessary, these compositions may containauxiliary substances, such as preserving, stabilizing, wetting,emulsifying agents and the like, as well as salts for varying theosmotic pressure, butters, etc. They may also contain, in combination,other useful substances, particularly antihypertensive agents, such asRau'wolfia alkaloids, e.g. reserpine, deserpidine, rescinnamine and thelike, semisynthetic Rauwolfia alkaloids, e.g. syrosingopine and thelike, veratrum alkaloids, e.g. protoveratine A, protoveratine B and thelike, synthetic antihypertensive drugs, e.g. hydralazine, dihydralazine,guanethidine and the like, ganglionic blockers, e.g. chlorisondamine andthe like, or any other useful substances, such as potassium chloride andthe like.

The compounds of this invention are prepared according to methods knownper se, for example, by cyclizing a 2-sulfamyl-N-(carbocyclic aryl-loweralkanoyl)-aniline, particularly a compound of the formula:

or a 2-(N-acyl-sulfamyl) N (carbocyclic aryl-lower alkanoyl)-aniline,particularly a compound of the formula:

in which n, R and R have the previously-given meaning, and acyl,particularly the acyl radical of the formula Ac, stands for the acylradical of an organic carboxylic acid, to form the desired3-(carbocyclic aryl-lower alkyl)- 1,2,4-benzothiadiazine 1,1 dioxidecompound, particularly a compound having one of the formulae:

in which 11, R and R have the previously-given meaning, and, if desired,converting a resulting salt into the free compound, and/or, if desired,converting a resulting compound into a salt thereof.

The acyl radical of an organic carboxylic acid, which substitutes thesulfamyl group, and which is represented in the above formula by theradical Ac, is, for example, the acyl radical of a carbocyclic arylcarboxylic acid and has more especially the formula CO(C H )R in which nand R have the previously-given meaning. However, it may also stand forthe acyl radical of any other suitable organic carboxylic acid, such asa lower alkanoic acid, e.g. acetic, propionic acid and the like.

Cyclization of the 2-sulfamyl-N-(carbocyclic aryllower alkanoyl)-aniline is carried out at an elevated temperature, preferably at atemperature between 75 and 200. The cyclization may take place in theabsence or in the presence of an inert solvent, such as, for example,ethanol, propanol, diethyleneglycol dimethyl ether,N,N-dimethylformamide and the like, if necessary,

in a closed vessel under pressure, and/or in the atmosin which R R and Rhave the previously-given meaning.

The starting materials may be prepared, for example, by reactingaZ-SuIfamyI-aniline, especially a compound of the formula:

S O ZNHg R2 I or a Z-(N-acyl-sulfarnyl)-aniline, particularly a compoundof the formula:

in which R and Ac have the previously-given meaning, with the halide,particularly chloride, or anhydride of a carbocyclic aryl carboxylicacid, particularly an acid of the formula:

in which n and R have the previously-given meaning.

The acylation of the sulfamyl-nitrogen may take place simultaneouslywith the desired acylation of the anilinenitrogen. Whenever thetreatment with the acylating reagent is carried out in the presence ofan inert, slightly polar to non-polar organic solvent, such as anaromatic hydrocarbon, an ether and the like, the mono-acylated product,in which the aniline-nitrogen is acylated, is obtained. Any acidgenerated during the acylation reaction may be neutralized by adding asuitable reagent, e.g. sodium acetate and the like. Di-acylation occurswhenever the acylation is used in an excess amount and in the presenceof a base, such as a tertiary amine, e.g. N,N,N-triethylamine and thelike, or a heterocyclic base, e.g. pyridine and the like.

The compounds of this invention may also be prepared by reacting a2-sulfamyl-aniline compound, particularly a compound of the formula:

ASOZNHZ R 1 in which R has the previously-given meaning, with anortho-ester, especially a lower alkyl ortho-ester, of a carbocyclicaryl-lower alkanoic acid, particularly an orthoester of the formula:

in which n and R have the previously-given meaning, and R representslower alkyl, and, if desired, carrying out the optional steps.

As mentioned hereinbefore, an ortho-ester of a carbocyclic aryl-loweralkanoic acid is preferably a lower alkyl ortho-ester, in which loweralkyl (represented in the above formula by R) has from one to fourcarbon atoms and stands for methyl, ethyl, n-propyl, isopropyl, n-butyland the like; ethyl ortho-esters are the preferred reagents. The abovereaction is preferably carried out at an elevated temperature, and inthe presence of an inert organic solvent; if necesary, it may beperformed in a closed vessel under pressure, and/or in the atmosphere ofan inert gas, e.g. nitrogen and the like.

The resulting product may be obtained in the form of the free compoundor as a salt thereof. A resulting meal, such as an alkali metal, saltmay be converted into the free compound by treatment with an acidicreagent, such as an aqueous mineral acid, e.g. hydrochloric, sulfuricacid and the like. A resulting free compound may be converted into ametal, particularly into an alkali metal salt, for example, by treatmentwith an alkali metal hydroxide, e.g. sodium hydroxide, potassiumhydroxide and the like, in the presence of a suitable inert solvent,such as in a lower alkanol, e.g. methanol, ethanol and the like, or inwater and evaporating the solvent, or by reacting the free compound, forexample, in an ether, e.g. p-dioxane, diethyleneglycol dimethylether andthe like, solution, with a metal, particularly an alkali metal, hydrideor a metal, particularly an alkali metal, amide, e.g. sodium hydride,potassium hydride, sodium amide, potassium amide and the like.

The invention also comprises any modification of the process wherein acompound obtainable as an intermediate at any state of the process isused as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferablyused which lead to final products mentioned in the beginning aspreferred embodiments of the invention.

The following examples illustrate the invention; they are not to beconstrued as being limitations thereon. Temperatures are given indegrees Centigrade.

Example 1 A mixture of 5.0 g. of 4-chloro-Z-sulfamyl-aniline and 3.45 g.of phenyl-acetic acid chloride in benzene contain:

5. ing 2.2 g. of sodium acetate is heated on the steam bath. Theprecipitate is filtered off, and the benzene solution is evaporated toyield the desired 4-ch1oro-N-pheny1- acetyl-2-sulfamyl-aniline of theformula:

Cl SOzNHz The latter is dissolved in N,N-dimethylformamide and thesolution is refluxed for one hour. Water is added, and, upon chilling,the desired 3-benzyl-7-chl oro-1,2,4-benzothiadiazine-1,1-dioxide havingone of the formulae:

N Q H precipitates, is collected and recrystallized from ethanol.

Example 2 A mixture of 4.0 g. of 5-chloro-Z-sulfamyl-aniline and 2.78 g.of phenyl acetic acid chloride in a benzene solution containing 1.75 g.of sodium acetate, when reacted as shown in Example 1, yields theS-chloro-N-phenylacetyl- 2-sulfamyl-aniline, which is ring-closed to thedesired benzyl-6-chloro-1,2,4-benzothiadiazine-1,l-dioxide having one ofthe formulae:

and

by refluxing an N,N-dimethylformamide solution thereof.

Other compounds, such as, for example, the

6 3- 1, (4-isopropyl-phenyl) -ethyl] -7-trifluoromethyl-1,2,4-

benzothiadiazine-1,1-dioxide,7-chloro-3-[1-(4-ethoxy-phenyl)-ethyl]-1,2,4-benzothiadiazine-1,1-dioxideand the like,

are prepared according to the previously-outlined procedure illustratedin the above examples.

Example 3 An aqueous solution of the sodium salt of 3-benZyl-7-chloro-1,2,4-benzothiadiazine-1,l-dioxide is prepared by dissolving 0.5g. of 3-benZyl-7-chloro-1,2,4-benzothiadiazine-1,1-dioxide in a solutionof an equivalent amount of sodium hydroxide in water.

What is claimed is:

1. A compound having one of the formulae:

in which one of the groups R and R represents a member selected from thegroup consisting of chloro, bromo and trifluoromethyl, and the otherstands for hydrogen, and R represents a member selected from the groupconsisting of hydrogen and methyl.

2. An alkali metal salt of a compound having one of the formulae:

in which one of the groups R and R represents a member selected from thegroup consisting of chloro, bromo and trifluoromethyl, and the otherstands for hydrogen, and R represents a member selected from the groupconsisting of hydrogen and methyl.

3. 3-benzyl-7-chloro-1,2,4-benzothiadiazine-l,l-dioxide. 4.3-benZyl-6-chloro-1,2,4-benzothiadiazine-1,l-dioxide. 5. Apharmaceutical preparation, which contains as the essential ingredient apharmacologically effective amount of a compound having one of theformulae:

NH R2 I l C(OnH2n) Ri and 7 8 in which the letter It stands for aninteger from 1 to 4, 2,794,834 6/57 Randall et al. 2 260556 bothinclusive R represents a member selected from the 2,809,194 10/57Novello 260-243 group consisting of phenyl, and R represents hydrogen, I2,910,473 10/59 Novello 260243 halogeno, lower alkyl, trifiuoromethyland nitro, and an 2,910,476 10/59 Novello 260-243 alkali metal saltthereof, together With an inert carrier. 5 2,986,573 5/61 Topliss et a1.260-243 OTHER REFERENCES Wertheim; Textbook of Organic Chemistry, pages763-764.

References Cited by the Examiner UNITED STATES PATENTS 2,059,903 11/36Petitcolas 260556 2,388,529 11/45 DAlelio et a1. 260-566 NICHOLAS s.Rlzzo, Primary Examiner. 2,726,264 12/55 Gregory 260-556 UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 210,347 October 5,1965 Lincoln Harvey Werner et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 7 lines 2 and 3 for "both inclusive R represents a memberselected from the group consisting of phenyl, and R representshydrogen," read both inclusive, R represents phenyl, and R represents amember selected from the group consisting of hydrogen,

Signed and sealed this 19th day of July 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A COMPOUND HAVING ONE OF THE FORMULAE:
 5. A PHARMACEUTICALPREPARATION, WHICH CONTAINS AS THE ESSENTIAL INGREDIENT APHARMACOLOGICALLY EFFECTIVE AMOUNT OF A COMPOUND HAVING ONE OF THEFORMULAE: